Abstract A124: Preclinical characterization of AB154, a fully humanized anti-TIGIT antibody, for use in combination therapies

Abstract

Abstract TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an inhibitory receptor that is expressed on natural killer (NK) cells, CD8+ T-cells, and immunosuppressive regulatory T-cells (Treg). DNAM-1 (DNAX Accessory Molecule-1; CD226) is an activating receptor found on NK cells, monocytes and a subset of T-cells. TIGIT and DNAM-1 are paired receptors that compete for shared ligands CD155 (PVR) and CD112 (Nectin-2) expressed by tumor and antigen-presenting cells. TIGIT binding to CD155 or CD112 results in immune suppression, whereas binding of DNAM-1 to the same ligands mediates immune activation. As malignancies progress, high TIGIT expression often occurs alongside the upregulation of other immune checkpoint proteins and markers of T-cell exhaustion such as PD-1 (Programmed Death-1). We have developed AB154 to inhibit TIGIT and shift the balance in the tumor microenvironment towards a more productive anticancer response. Blockade of multiple immune checkpoint proteins can confer effective and durable responses in the treatment of cancer. Data assembled from TCGA (The Cancer Genome Atlas) identified numerous tumor types in which TIGIT is co-expressed with PD-1. In these tumors, TIGIT and PD-1 were significantly upregulated compared to normal adjacent tissue. Immunophenotyping performed on human tumor infiltrating lymphocytes demonstrated a strong correlation between TIGIT and PD-1 co-expression on specific immune cells including CD8+ T-cells and Treg cells. AB154 is a fully humanized antibody that blocks human TIGIT with sub-nanomolar affinity, as determined using a CHO.hTIGIT over-expressing cell line and primary human T-cells. Functional consequences of blocking TIGIT/CD155 interactions in combination with anti-PD-1 or anti-PD-L1 were evaluated using mixed lymphocyte reactions (MLR). Briefly, we show here that co-cultures of GM-CSF/IL-4-differentiated CD155+ PD-L1+ monocytes and TIGIT+ CD4+ T-cells, in the presence of AB154, significantly increased IFN-gamma secretion when combined with anti-PD-1 or anti-PD-L1 blocking antibodies relative to each monotherapy. Understanding pharmacokinetic (PK) and pharmacodynamic (PD) relationships enables the choice of a dosing regimen that provides adequate target coverage. To evaluate the PD effects of AB154 in clinical samples, we developed a multicolor flow cytometry-based assay that utilizes an anti-TIGIT antibody that is competitive with AB154 to determine receptor occupancy. In human whole blood, ex vivo addition of AB154 achieved complete inhibition of TIGIT. Analysis of blood mononuclear cells, including CD8+ and CD4+ T-cells, Treg and NK cells, demonstrated target engagement by AB154 suitable for clinical development. In addition, we examined TIGIT receptor occupancy of AB154 (added to whole blood ex vivo) in a small cohort of non-small cell lung cancer (NSCLC) patients treated with anti-PD-1 antibody pembrolizumab. In these samples, TIGIT receptor occupancy by AB154 was comparable to that obtained with healthy donor blood samples. The data presented here provide: 1) rationale for combining AB154 with our in-house developed anti-PD-1 antibody (AB122) in upcoming clinical trials, and 2) methodology to evaluate TIGIT receptor occupancy in the upcoming AB154 dose escalation studies. AB154 is expected to enter clinical trials in 2018. Citation Format: Amy E. Anderson, Annette Becker, FangFang Yin, Hema Singh, Xiaoning Zhao, Lisa Seitz, Rick Stanton, Nigel P.C. Walker, Joanne B.L. Tan. Preclinical characterization of AB154, a fully humanized anti-TIGIT antibody, for use in combination therapies [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A124.